The use of gene transfer technologies and the mouse as a model of human respiratory diseases aptlysummarizes the research program of the candidate, James (Jamie) J-.ee, Ph.D. This work forms the basis of the candidate's immediate career goals of expanding the breadth of his laboratory to includeincreasinglycomplex assessmentsof physiologically relevant endpoints of pathology. The achievement of these immediate goals, in turn, support the long term goals, including (i) To move the orientation of the lab from a molecular biology perspective to a physiology-based program and (ii)To expand the educational activities in mouse research within the Mayo Foundation, and Mayo ClinicArizona in particular,and to includethe regional graduate program at ArizonaState Uni versity. The institutional support and commitmentto research and graduate education offered byMayo Clinic, together with the expanding local university graduate programs in biomedical research, represent unique opportunities to create a collaborative center of focused efforts using the mouse as a model system of human disease research. A critical objective of this career development plan is to recruit and train motivatedstudents and fellows, capitalizing on the success of the laboratory's research activities.The goals of the researchproposal are to define the role(s) of eosinophils and eosinophil effector functions mediating allergic inflammation and, therefore, their roles in the development of pulmonary pathologies. The proposal exploits unique eosinophil- specific reagents and novel transgenic and gene knockout mice we have created in our studies ofeosinophil biology. The objectives will be achieved through the completion of the following aims: (1) To determine unequivocally the contribution(s)of eosinophils to the pulmonarypathologies arising in a transgenic model of asthma generated by the co-expression of JJL-5 and eotaxin-2;(2) To define mechanisms of eosinophil effector functions responsible for the pulmonarypathologiesoccurring in the IL-5/eotaxin-2 transgenicmodel of asthma; (3) To determine if degranulation and the release of granule proteins represents a mechanism by which eosinophils contribute to the pathologies arising in the IL-5/eotaxin-2 transgenic model of asthma.